Field of the Invention
The present invention relates to 4-arylpiperazine compounds. These compounds function as opioid receptor antagonists, and can be used to treat a variety of disease states.
Description of the Background
The opioid receptors, μ, δ, κ, and the opioid-like receptor ORL-1 belong to the super family of G-protein coupled receptors (GPCRs) that possess seven helical trans-membrane spanning domains in their architecture.1 The majority of research efforts focused upon this group of proteins has been directed toward the preceptor since it mediates the actions of both the opiate and opioid analgesics such as morphine and fentanyl, respectively.2 However, over the years it has become increasingly clear that the entire family of proteins is actively involved in a host of biological processes.2 Furthermore, the advent of selective antagonists has demonstrated that pharmacotherapeutic opportunities exist via both negative and positive modulation of this receptor family.3-8 
The opioid receptor system has been extensively studied, and thousands of compounds have been synthesized and evaluated by in vitro binding and functional assays as well as by animal models.2 An integral part of the effort to characterize the opioid receptor system has been the discovery of potent, pure antagonists. Naloxone (1a) and naltrexone (1b), both competitive antagonists at μ, δ, and κ opioid receptors,9 have been extensively used as pharmacological tools to identify and characterize opioid systems (see FIG. 1 for structures). Additionally, naloxone is approved to treat heroin overdose and to reverse respiratory depression caused by morphine.9 Naltrexone is used to treat heroin and alcohol abuse.
In 1978, Zimmerman and co-workers reported the discovery of a structurally unique series of opioid receptor pure antagonists based on N-substituted analogues of 3,4-dimethyl-4-(3-hydroxyphenyl)piperidine (2a, LY272922).10 Unlike naloxone (1a) and naltrexone (1b) where the antagonist activity is dependent on the N-allyl or N-cyclopropylmethyl substituent, all N-substituted trans-3,4-dimethyl-4-(3-hydroxyphenyl)piperidines (2) including the N-methyl analogue 2b are opioid receptor pure antagonists.10-14 A few of the more interesting analogues include alvimopan (3), which is an FDA-approved drug for GI motility disorder,15 LY255,582 (2d),13,16 which was developed to treat obesity, and the selective κ opioid receptor antagonist JDTic (4),6-8,17 which shows activity in rat models of depression,18 anxiety,19 and stress-induced cocaine relapse.18 JDTic appears to be a promising therapeutic.
Komoto et al. reported structures like 6a-f in a paper entitled “New μ-Opioid Receptor Agonists with Piperazine Moiety.” They do not describe that the compounds have opioid receptor antagonistic efficacy.20 The compounds are synthesized by a route similar to that used to prepare 5a-j. At present, the opiate class, represented by naloxone (1a), naltrexone (1b), and the N-substituted 3,4-dimethyl-4-(3-hydroxyphenyl)piperidines, represented by alvimopan, LY255,582, and JDTic, are the only two classes of nonpeptide pure opioid receptor antagonists known. The discovery that 3-[4-(substituted piperazine-yl)]phenols (5) as described herein are pure opioid receptor antagonists adds a third example of this important class of compounds.
Studies with selective κ opioid antagonists have shown that this system is intimately involved in brain processes that relate to stress, fear, and anxiety as well as reward-seeking behavior. Studies have shown that JDTic (4) and nor-BNI, another κ opioid selective antagonist, dose-dependently reduce fear and stress-induced responses in multiple behavioral paradigms with rodents (immobility in the forced-swim assay,18,21 reduction of exploratory behavior in the elevated plus maze, and fear-potentiated startle).19 Furthermore, selective κ antagonists have been shown to reduce stress-induced reinstatement of cocaine self-administration in rats,18 to block the stress-induced potentiation of cocaine place preference conditioning,22-24 to decrease dependence-induced ethanol self-administration,25 to diminish deprivation-induced eating in rats,26 and to prevent pre-pulse inhibition mediated by U50,488.27 These observations regarding the behavioral consequences of receptor blockade in several animal tests suggest that κ antagonists will be useful for treating anxiety, depression, schizophrenia, addiction, and eating disorders.
Previously reported non-selective opioid receptor antagonists such as LY255582 have been found to increase metabolic energy consumption and reduce the weight in obese rats while maintaining muscle mass. These reports suggest that opioid receptor antagonists may be useful in preventing, treating, and/or ameliorating the effect of obesity. Eli Lilly and Company has developed new classes of opioid receptor antagonists that interact with the μ, δ, and κ receptors (termed non-selective) as potential pharmacotherapies to treat obesity and related diseases.28,29 The Lilly patents suggest that such compounds will be useful for the treatment and/or prophylaxis of obesity and related diseases including eating disorders (bulimia, anorexia nervosa, etc.), diabetes, diabetic complications, diabetic retinopathy, sexual/reproductive disorders, depression, anxiety, epileptic seizure, hypertension, cerebral hemorrhage, congestive heart failure, sleeping disorders, atherosclerosis, rheumatoid arthritis, stroke, hyperlipidemia, hypertriglycemia, hyperglycemia, hyperlipoproteinemia, substance abuse, drug overdose, compulsive behavior disorders (such as paw licking in dog), and addictive behaviors such as for example gambling and alcoholism.